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BACKGROUND: Dravet syndrome (DS) is a severe and treatment-resistant epileptic encephalopathy, most commonly caused by de novo mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene. Patients with DS often present with febrile seizures. It has been reported that Scn1a mutant mice have the risk for hyperthermia-induced clonic seizures similar to those observed in patients with DS. Using our heating protocol with an incubator, we evaluated the effects of antiseizure medications on the incidence of hyperthermia-induced clonic seizures in mutant Scn1a knock-in (KI)/+ mice. METHODS: For clonic seizure induction in Scn1a KI/+ mice, each mouse was placed into an incubator (38°C-40°C) and observed for 15 min. Antiseizure medications were administered orally 30 min prior to the experiment. The time to seizure onset and the incidence of clonic seizures were analyzed to evaluate and compare the antiseizure effects among treatment groups. RESULTS: Our incubation system increased the body temperature of mice and induced clonic seizures in Scn1a KI/+ mice. Clobazam (CLB) and valproate (VPA) significantly reduced the incidence of hyperthermia-induced clonic seizures in Scn1a KI/+ mice, with 50% effective dose (ED50) values of 1.94 mg/kg (95% confidence interval [CI]: 0.93-3.89 mg/kg) and 255.87 mg/kg (95% CI: 188.66-356.85 mg/kg) respectively, and prolonged the time to seizure onset. In contrast, lamotrigine (LTG), a sodium channel blocker, did not reduce the incidence of hyperthermia-induced seizures. CLB and LTG did not affect the body temperature. VPA decreased the body temperature compared to the vehicle-treated mice before and after incubation. CONCLUSION: These results reflect clinical findings that CLB and VPA suppress, but LTG does not suppress seizures in patients with DS. Our data demonstrate the validity of our test system to induce hyperthermia-induced seizures and to evaluate the efficacy of antiseizure medications in Scn1a KI/+ mice.

OBJECTIVE: To systematically review the current research progress on clobazam in pediatric antiepileptic therapy, focusing on its pharmacological mechanisms, pharmacokinetic properties, clinical efficacy, safety profile, and approaches to individualized treatment, with particular emphasis on the influence of CYP2C19 genetic polymorphisms on pharmacokinetics and therapeutic outcomes, and to provide a comprehensive reference for the rational clinical use of clobazam. METHODS: This article comprehensively reviews the current research progress on clobazam in pediatric antiepileptic therapy, including evidence of efficacy across different epilepsy syndromes, strategies for managing drug-drug interactions, and individualized dosing regimens based on genotyping and therapeutic drug monitoring. RESULTS: Clobazam is a 1,5-benzodiazepine used as an antiseizure medication. Compared with classical 1,4-benzodiazepines, it demonstrates greater efficacy and fewer sedative adverse effects. Clobazam was approved by the U.S. Food and Drug Administration (FDA) in 2011 as an adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥2 years. Since then, it has been increasingly used as adjunctive therapy for several pediatric epilepsy syndromes, including Dravet syndrome (DS), epilepsy with myoclonic-atonic seizures (EMAS), and epileptic encephalopathy with spike-wave activation during sleep. CYP2C19 genetic polymorphisms significantly influence its pharmacokinetics and therapeutic outcomes. Across the reviewed studies, adjunctive clobazam achieved ≥50% seizure reduction in approximately 53% of children and seizure freedom in approximately 24%. Efficacy was highest in LGS, supported by randomized controlled trials, while evidence for other syndromes was largely observational. CYP2C19 poor metabolizer status significantly increased N-desmethylclobazam exposure, supporting genotype-guided dose initiation. CONCLUSION: Clobazam demonstrates consistent efficacy as adjunctive therapy in pediatric drug-resistant epilepsy, with the strongest evidence supporting its use in LGS. Individualized treatment informed by CYP2C19 genotyping and therapeutic drug monitoring can optimize clinical outcomes. This review provides a comprehensive reference for the rational clinical use of clobazam.

OBJECTIVE: To determine the extent to which electroclinical information available at initial evaluation allows classification of idiopathic generalized epilepsy (IGE) syndromes, and to assess the contributions of seizure semiology and age at seizure onset to early syndromic diagnosis. METHODS: We prospectively analyzed a cohort of patients with new-onset seizures who underwent a structured clinical evaluation, including detailed history-taking, 3-h video-EEG, and epilepsy-protocol MRI. Seizure semiology was assessed at three levels: index seizure, initial seizure type, and seizure types identified at initial evaluation. Syndromic classification followed International League Against Epilepsy criteria. Final electroclinical diagnosis, established after longitudinal follow-up, served as reference. Within patients ultimately diagnosed with one of the four IGE syndromes, baseline data were used to determine whether the final syndrome could be assigned at initial evaluation. RESULTS: Of 2699 patients evaluated, 498 (18.4%) met criteria for genetic generalized epilepsy, of whom 401 (80.5%) were classified as having one of the IGE syndromes. Based on initial evaluation, the correct syndrome could be assigned in 366 patients (91.3%), whereas 7 (1.7%) would have been misclassified and 28 (7.0%) were not assignable. Non-assignability was confined to absence epilepsies, reflecting overlap between childhood (CAE) and juvenile absence epilepsy (JAE), whereas misclassification occurred only in juvenile myoclonic epilepsy (JME) presenting with isolated generalized tonic-clonic (GTC) seizures. Classification based on the index seizure alone showed limited accuracy (63.6%), whereas incorporation of seizure types identified through structured history improved classification to 95.0%. Myoclonic seizures were highly specific for JME, whereas absence and GTC seizures required integration with additional features. Age at seizure onset strongly differentiated CAE from JAE (AUC 0.935). SIGNIFICANCE: Electroclinical classification of IGE syndromes is frequently achievable at initial evaluation when based on seizure semiology and age at onset. When classification is not possible, limitations follow predictable electroclinical patterns, supporting a structured, history-driven diagnostic approach. PLAIN LANGUAGE SUMMARY: This study examined how accurately doctors can identify specific types of generalized epilepsy when patients are first evaluated. Among 401 patients with generalized epilepsy, the correct epilepsy syndrome could be identified in more than 90% at the first visit. Looking beyond the first seizure and asking about all seizure types together with age at seizure onset greatly improved diagnosis. While some overlap exists between specific types (like childhood versus juvenile absence epilepsy), a thorough clinical evaluation from the start provides reliable diagnostic direction for patients and supports early and accurate diagnosis.

RATIONALE: Hormones such as estrogen and progesterone influence seizure thresholds resulting in catamenial epilepsy in a subset of women with epilepsy. While prior studies assessing the correlation between menarche and seizure onset have found mixed results, little is known about the effects of puberty on seizure burden in patients with developmental and epileptic encephalopathies, such as Lennox-Gastaut syndrome (LGS). Determining whether seizure burden in LGS is affected by pubertal changes such as menarche will inform prognosis and anticipatory guidance for caregivers of patients. METHODS: A single-center retrospective chart review of female patients with LGS who had a documented age of menarche and who had been evaluated at a single tertiary care children's hospital between 2013-2023 was performed. Menarche was used as a proxy for puberty. Seizure type, frequency, number of anti-seizure medications, and change in anti-seizure medications were recorded yearly between the ages of 5-21 years. Statistical analysis with cumulative logit mixed models was used to estimate the odds of a patient having higher seizure frequency by seizure type. A linear mixed model was used to assess change in antiseizure medications. RESULTS: A total of 22 patients met inclusion criteria. Menarche was not independently statistically significantly associated with increased overall seizure when controlling for age (OR 0.58, p = 0.195). However, age was independently positively associated with seizure frequency (OR 1.16 per year, p = 0.002). When controlling for age, most individual seizure types (non-motor, atonic, tonic, myoclonic, clonic, status epilepticus) did not significantly increase with menarche. Total number of antiseizure medications (ASMs) used significantly increased after menarche by an estimated 0.43 ASMs (p = 0.026), when controlling for age. CONCLUSIONS: After controlling for age, menarche in patients with LGS did not correlate with increased seizure frequency in total or if stratified by specific seizure types. However, overall seizure frequency and anti-seizure medication usage increased with age, suggesting a gradual worsening of epilepsy over adolescence. These data provide important information regarding the clinical course of LGS which may aid in both medical management and in anticipatory guidance for families as their children enter adolescence. Further study is needed for deeper understanding of long-term outcomes of LGS, and how age and puberty may affect seizures in males with LGS.

The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and disrupted excitatory/inhibitory (E/I) balance. Single-cell RNA sequencing analysis of ventral EPM1-COs revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities. We demonstrated that this misspecification is driven by a functional alteration of the ventral signaling niche, resulting from impaired EV dynamics and altered protein cargo. Mechanistically, we identified Sonic Hedgehog (SHH) as a direct physical interactor of CSTB and demonstrated that CSTB deficiency leads to reduced SHH content and secretion. Our findings establish CSTB as a safeguard of ventral patterning and identify the CSTB-SHH-EV axis as a potential therapeutic target for mitigating the E/I imbalance associated with EPM1.